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Home , Myoclonus, Parkinsonism, Restless legs syndrome

J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.71.2.143 on 1 August 2001. Downloaded from J Neurol Neurosurg Psychiatry 2001;71:143–146 143

EDITORIAL

Restless legs

The term (RLS) was first intro- general population to 58% in a subpopulation of subjects duced by Karl A Ekbom, a Swedish neurologist and over 60 years old.10 It should be emphasised that PLMS surgeon, in 1945, although the earliest description of rest- occur in various disorders and other neurological less legs associated with sleep disabilities possibly came and may increase with age, whereas RLS remains from Sir Thomas Willis, an English physician, in 1672.12 a clinical diagnosis by definition.11 More recently, abnormal involuntary movements during sleep such as nocturnal (subsequently termed periodic limb movements during sleep (PLMS)) have been Pathophysiology and clinical associations reported to be associated with RLS.34 The underlying causes of RLS or PLMS remain unclear and as such various aetiologies including central and peripheral nervous systems, vascular, genetic, iatrogenic, Epidemiology and metabolic components have been proposed (table 1). Surveys in the white population suggest that adult The central system, particularly the striato- prevalence figures of RLS may range between 5% and nigral system, has been implicated and this hypothesis has 15%.5–7 The prevalence seems to increase with age, been supported by the beneficial eVects of various although retrospective assessments indicate that onset of dopaminergic agents in the treatment of RLS. Functional the syndrome may occur before the age of 20 in up to 43% imaging studies with SPECT and PET techniques have of adult cases.89 The MEMO study, a population based shown reduced striatal D2 receptor binding using survey of an elderly population, reported a higher 123I-IBZM and 11C-raclopride, suggesting postsynaptic prevalence of RLS in women, which however, did not dopaminergic dysfunction in patients with RLS during change with age, unlike men.7 There are currently no data sleep.12 13 Two of three 18F-DOPA PET studies have also available on prevalence of RLS in other ethnic groups such shown a slight but significant decrease in striatal 18F-DOPA http://jnnp.bmj.com/ as Asian or black populations. Periodic limb movements in uptake in patients with PLMS-RLS compared with healthy sleep were first reported by Lugaresi et al, who showed controls.13–15 A state dependent decrease in cerebral blood polysomnographically recorded PLMS (more than five/ flow in the caudate nuclei and increase in the anterior cin- hour) in up to 87.8% of patients with RLS.4 Prevalence gulate gyrus during increasing pain level has been reported estimates of PLMS are variable and range from 6% in the in a patient with familial RLS.16 A high resolution fMRI

Table 1 Pathophysiological basis and conditions thought to be associated with restless legs syndrome (RLS) on September 26, 2021 by guest. Protected copyright. Idiopathic RLS: RLS+PLM Central dopaminergic dysfunction: Presynaptic (caudate+putamen) Postsynaptic (D2) Cerebellar and thalamic activation RLS+SLD+PLM Diencephalodopaminergic dysfunction Red nucleus activation PLM+RLS Spinal origin Facilitation of spinal flexor reflexes RLS Metabolic Low brain iron content Familial Genetic form Positive family history Secondary RLS: Renal failure and uraemia Iron deficiency anaemia Vitamin B12 deficiency Rheumatoid Sjogren’s syndrome mellitus Movement disorders: related related Gilles de la Tourette’s syndrome Attention deficit hyperactivity disorder Mood related: related : Sensory polyneuropathy Hereditary motor sensory neuropathy (CMT 2) Pregnancy

www.jnnp.com J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.71.2.143 on 1 August 2001. Downloaded from 144 Chaudhuri, Appiah-Kubi, Trenkwalder

Table 2 Criteria for diagnosis of idiopathic restless legs syndrome (RLS)

Minimum diagnostic criteria Additional features Desire to move limbs, usually associated with para/dysaesthesia Sleep disturbance Motor restlessness Periodic limb movements in sleep Symptoms worse or exclusively present at rest: partial/temporary relief with activity Neurological examination normal Symptoms worse in the evening or at night Chronic symptoms with exacerbations and remissions Positive family history

International Restless Legs Syndrome Study Group.11 Response to dopaminergic agents, although often present, is not regarded as a criteria for diagnosis of idiopathic RLS. study reported possible cerebral generators underlying minimal criteria for diagnosis of RLS has been recom- sensory leg discomfort and PLMS in patients with RLS, mended by the international RLS study group (table 2).11 there being bilateral cerebellar and contralateral thalamic Presenting features usually include sensory symptoms activation during sensory leg discomfort, and additional described as creeping, crawling, tingling, burning, or pain activation of the red nucleus and brain stem during in the lower limbs associated with a compulsion to move combined sensory leg discomfort and PLM.17 the legs. Symptoms occur most commonly when lying or The relation between the occurrence of PLM and RLS is resting and commonly frustrate and interrupt sleep. There also unclear. Testing spinal flexor reflex excitability in also seems to be a circadian pattern to symptoms, which patients with RLS, Bara-Jimenez et al18 suggested that are worse at night, independently of an association with PLMS and spinal flexor reflexes share a common spinal sleep or rest.10 15 Movement or voluntary actions such as origin, and disinhibition of reticulospinal excitatory pacing, shaking, or rubbing the limbs usually relieve symp- responses may lead to pathological recruitment of spinal toms temporarily, but add to sleep disturbance.31 motor neurons.17 18 Spinal flexor reflexes seem to be under Periodic limb movements in sleep, defined as repetitive partial dopaminergic control and levodopa depresses both flexing of lower limb joints (hip, knee or ankle) and dorsi- facilitatory and inhibitory flexor reflex aVerents.19 Thus the flexion or fanning of toes, for periods of 0.5–5 seconds at concept that PLM may arise from loss of supraspinal intervals of 5–90 seconds32 is often associated with RLS. inhibitory impulses resulting in enhanced spinal flexor Daytime leg movements may also occur in severe RLS; reflex facilitation is consistent with the dopaminergic dys- these are also sometimes periodic in nature. function hypothesis in RLS. The diVerential diagnosis is broad and includes other A metabolic basis of secondary RLS has been postulated conditions involving motor restlessness with sensory and a common association of RLS is iron deficiency anae- symptoms or disagreeable feelings in the legs. These mia.20 Studies of CSF concentrations of and trans- include those with an inconsistent association with rest or ferrin in RLS have shown reduced CSF ferritin and sleep (panic attacks, , and painful legs and moving increased transferrin concentrations in idiopathic RLS toes syndrome33 and generalised restlessness similar to assuming a low brain iron content in RLS.20 Serum iron akathisia). The uncommon syndrome of painful legs and concentrations exhibit circadian variation with up to a 50% moving toes has a similar distribution but is not relieved by drop in iron concentration at night when the symptoms of movement. “Vesper’s curse” is a condition associated with RLS are most obvious.21 Furthermore, iron is also required congestive heart failure, in which engorgement of the lum- as a for hydroxylation of tyrosine hydroxylase, bar veins at night brings about a transient stenosis of the which is the rate limiting enzyme for produc- lumbar cord causing nocturnal pain in the lower limbs tion.22 Other metabolic correlates may be hypothyroidism23 extending to the lumbosacral region.34 Sensory symptoms 524 and diabetes mellitus. Restless legs syndrome has also in the lower limbs may also be due to polyneuropathies, http://jnnp.bmj.com/ been reported to occur in up to 25% of patients with pri- meralgia paraesthetica (compression of the lateral cutane- mary diagnosis of and Sjogren’s ous nerve of the thigh), or muscle irritation due to , syndrome although the association remains controversial.25 conditions which may or may not include a desire to move The issue of coexistence of RLS and Parkinson’s disease the limbs. Sleep onset myoclonus and nocturnal myo- is controversial and currently being investigated. An are other possibilities to consider in the diVerential increased PLM index has been reported in untreated diagnosis. patients with Parkinson’s disease.26 Misdiagnosis of RLS

may occur due to nocturnal and akathisia in on September 26, 2021 by guest. Protected copyright. patients with Parkinson’s disease treated with levodopa. Diagnosis and investigation A genetic basis for RLS is supported by studies reporting a positive family history in 63%-92% of patients with idio- The frequency of the recorded PLMS correlates strongly pathic disease10 and an autosomal dominant pattern of although indirectly with RLS, and is a useful measure for inheritance has been suggested. No gene linkage to RLS diagnosing RLS and monitoring of treatment.9 PLM may has yet been found. Studies in kindreds of familial RLS be detected by EMG recordings, usually of the tibialis suggest anticipation and variable penetrance.27 28 The syn- anterior muscle. PLM scoring should be done according to drome has also been found in patients with spinocerebellar the American Association rules32; per hour ataxia (type 3) assuming a possible role of CAG repeat of sleep, a pathological value is defined as more than five sequences in the SCA 3 gene.29 PLM/hour of sleep. Evidence of arousal from EEG record- ings is incorporated to form the PLM arousal index—the Clinical features number of PLM events temporally associated with Restless legs syndrome may present with a wide range of arousal/hour. symptoms including unpleasant sensations between the ankle and knee, occasionally extending to involve the whole lower limb, or even the upper limbs. One study reported Other objective assessments of increased lower limb motor arm restlessness in 48.7% of patients with idiopathic RLS, activity include actigraphy and immobilisation tests. In particularly those with severe disease.30 Thus misdiagnosis actigraphy, muscle activity is monitored by a small portable is common and in some cases diagnosis may be consider- meter, usually worn at the ankle. Although avoiding the ably delayed. To help early and accurate diagnosis, the need for laboratory studies and allowing monitoring in the

www.jnnp.com J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.71.2.143 on 1 August 2001. Downloaded from Restless legs syndrome 145

Table 3 Treatment strategies for restless legs syndrome (RLS) Rebound phenomena are rare and consist of a worsening of symptoms in the early morning after nocturnal levodopa Drugs Dose range Specific issues application.38 Dopaminergic (usually first choice): Levodopa DCI 100–600 mg Rebound/augmentation DOPAMINE AGONISTS Evening or divided dose 7.5 mg (divided dose) Poor tolerance Virtually all dopamine agonists have been used for RLS 0.1–0.75 mg Single or two evening because of problems related to long term levodopa therapy doses in RLS. Four double blind, one single blind, and nine open 0.5–4 mg daily/twice daily DHEC 10–40 mg label trials involving various ergot and non-ergot agonists 1.5 mg Single evening dose have been published so far. A double blind placebo 1–4 mg Useful for augmentation controlled study using bromocriptine at a mean dose of 7.5 18–50 mg/12 h Overnight sc infusion 100–400 mg mg showed subjective benefit in 83.8% of cases, with Other drugs: decrease in PLMS.11 Another clinical study comparing Oxycodon 2.5–25 mg Propoxyphene 100–260 mg levodopa and bromocriptine suggested equivalent subjec- 0.5–2 mg evening dose Drowsiness tive improvement with both although tolerability seemed to Triazolam 0.125/0.25 mg be better with levodopa.39 Two open label trials using per- Nitrazepam 2.5–10 mg 100–600 mg Single/divided doses golide (0.1–0.75 mg) given in the evening as a single dose 300–2400 mg Quick dose escalation or two doses showed a sustained eVect through the night 0.15–0.9 mg with improvement of RLS. These findings have been con- Baclofen 20–80 mg Drowsiness/single dose Only in iron deficient patients: firmed in two further double blind studies, one comparing Iron oxide 100–200 mg/dose Intravenous pergolide (0.125–0.25 mg) and levodopa (250–500 mg), Iron sulphate 200 mg three times Oral which showed better subjective improvement and a greater daily eVect on PLMS (79% v 445%) with pergolide. Augmenta- tion induced by levodopa was also reversed after treatment patient’s own home, most actigraphical devices do not dif- with pergolide.40 Other studies, reported recently, include ferentiate between PLM and other involuntary movements reports of beneficial eVect on RLS with ropinirole (0.5–4 associated with apnoea. Only few systems can be used for mg once/twice/day), dihydroergocriptine (10–40 mg in recording PLM specifically.35 divided doses), pramipexole (1.5 mg as a single evening dose), cabergoline (1–4 mg as an evening dose) and IMMOBILISATION TESTS apomorphine (nocturnal subcutaneous infusion 18–48 41–43 Immobilisation tests, in which patients attempt to maintain mg). Of these, pramipexole has been examined in a a seated posture without moving their legs (suggested double blind fashion, with significant reduction of subjec- immobilisation test (SIT)), are used experimentally as the tive restlessness and PLMS, although the sleep architecture only objective tests to provoke waking RLS symptoms by remained unaltered. Cabergoline and ropinirole are forced rest.36 Another variant is the forced immobilisation currently undergoing double blind evaluation. Long term test (FIT) during which the legs are physically restrained (mean 7.8. months) eYcacy of pramipexole (0.25–0.75 while anterior tibial EMGs record PLM. This test is no mg) suggest continued eYcacy of pramipexole during the 30 longer recommended by us due to the discomfort of the follow up period. Cabergoline, the longest acting patients. (half life 65 hours), has the advantage of being active when given once a day. Open label studies suggest that cabergoline is well tolerated in patients with

Treatment severe RLS who have failed other therapies and also those http://jnnp.bmj.com/ Treatment strategies for RLS are diverse and mainly focus with augmentation.41 42 Other dopaminergic drugs re- on dopaminergic therapy (table 3). However, published ported to be of benefit in RLS include , evidence of RLS therapy is compounded by issues , and amantadine.44 surrounding (a) accuracy of diagnosis, (b) recruitment bias within study population, (c) lack of studies in multiethnic and younger subjects, (d) lack of parallel group studies. Opiates (laudanum) were used for the treatment of RLS in Non-pharmacological measures include advice on im- the 17th century and recently, opiates such as oxycodone11 provement of and avoidance of stimulants or and propoxyphene have shown beneficial eVects in four on September 26, 2021 by guest. Protected copyright. aggravating drugs (for example, caVeine, alcohol, antihista- small studies (two double blind placebo controlled) dimin- mines, certain ). In physiological condi- ishing both RLS and PLMS with symptomatic relief, tions such as pregnancy, symptoms may resolve after deliv- reversible by the antagonist naloxone.45 ery. In iron deficiency anaemia iron supplementation should be given first. Clonazepam has been most widely studied although others LEVODOPA such as triazolam and nitrazepam have also been studied. Fifteen published studies (eight double blind and seven Results of double blind crossover studies have been clinical series) in a relatively few patients (ranging from six variable, reporting either no or modest benefit in leg symp- to 32) using evening or divided dosing of standard toms and sleep. Overall, studies suggest that clonazepam levodopa at doses varying between 100 mg and 600 mg, can be helpful for treatment of RLS but considerable res- indicate that levodopa therapy consistently reduces PLMS ervations remain owing to the small sample size of studies and nocturnal RLS symptoms in the early part of the night, and the confounding eVect of benzodiazepines on sleep possibly secondary to the short half life of levodopa.10 Open variables. and controlled studies confirm the tolerability and subjec- tive benefit of levodopa therapy. The major problem with ANTIEPILEPTIC DRUGS levodopa therapy seems to be that of augmentation. Carbamazepine has been most widely studied, and recent Thereby, RLS symptoms occur earlier in the day after studies have used gabapentin. Open label studies with starting with levodopa treatment at night and RLS gabapentin also showed subjective improvement of RLS symptoms may also emerge in the trunk or upper limbs.37 symptoms between doses of 300 to 2000 mg/day. Thus

www.jnnp.com J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.71.2.143 on 1 August 2001. Downloaded from 146 Chaudhuri, Appiah-Kubi, Trenkwalder there seems to be some benefit from antiepileptic drugs, 11 Walters AS. Toward a better definition of restless legs syndrome. The Inter- national Restless Legs Syndrome Study Group. Mov Disord 1995;10:634– particularly with painful RLS although this may not 42. include improvement of PLMS. 12 Staedt J, Stoppe G, Kogler A, et al. Dopamine D2 receptor alteration in patients with periodic movements in sleep (nocturnal myoclonus). Journal of Neural Transmission General Section 1993;93:71–4. ADRENERGIC DRUGS 13 Turjanski N, Lees AJ, Brooks DJ. Striatal dopaminergic function in restless Those studied include propranolol and clonidine, which legs syndrome: 18F-dopa and 11C-raclopride PET studies. 1999;52:932–7. act to suppress noradrenergic activity. Clonidine at doses 14 Ruottinen HM, Partinen M, Hublin C, et al. An FDOPA PET study in between 0.15–0.9 mg/day seems to be eVective in patients with periodic limb and restless legs syndrome. Neurology 2000;54:502–4. suppressing RLS symptoms, including those due to 15 Trenkwalder C, Walters AS, Hening WA, et al. Positron emission uraemia as reported in one study. tomographic studies in restless legs syndrome. Mov Disord 1999;14:141–5. 16 San Pedro EC, Mountz JM, Mountz JD, et al. Familial painful restless legs syndrome correlates with pain dependent variation of blood flow to the BACLOFEN AND OTHER AGENTS caudate, and anterior cingulated gyrus. J Rheumatology 1998;25: 2270–5. Drugs such as baclofen and clonidine are only rarely used 17 Bucher SF, Seelos KC, Oertel WH, et al. Cerebral generators involved in the because dopaminergic agents and seem to reduce pathogenesis of the restless legs syndrome. Ann Neurol 1997;41:639–45. RLS symptoms suYciently with less side eVects. 18 Bara-Jimenez W, Aksu M, Sato GS, et al. Periodic limb movements in sleep. 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